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Lactobacillus for preventing recurrent urinary tract infections in women:

Meta-analysis

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Lactobacillus for preventing recurrent urinary
tract infections in women: meta-analysis
Peter M. Grin,1,2 Paulina M. Kowalewska,3 Waleed Alhazzani, MD,1
Alison E. Fox-Robichaud, MD1,2
1
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
2
Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
3
Medical Sciences Graduate Program, McMaster University, Hamilton, Ontario, Canada
GRIN PM, KOWALEWSKA PM, ALHAZZANI W,
FOX-ROBICHAUD AE. Lactobacillus for preventing
recurrent urinary tract infections in women: meta-
analysis. Can J Urol 2013;20(1):6607-6614.
Introduction: Urinary tract infections (UTIs) are the
most common infections affecting women, and often
recur. Lactobacillus probiotics could potentially replace
low dose, long term antibiotics as a safer prophylactic for
recurrent UTI (rUTI). This systematic review and meta-
analysis was performed to compile the results of existing
randomized clinical trials (RCTs) to determine the efficacy
of probiotic Lactobacillus species in preventing rUTI.
Materials and methods: MEDLINE and EMBASE
were searched from inception to July 2012 for RCTs
using a Lactobacillus prophylactic against rUTI in
premenopausal adult women. A random-effects model
meta-analysis was performed using a pooled risk ratio,
comparing incidence of rUTI in patients receiving
Lactobacillus to control.
Introduction
Urinary tract infection (UTI) is an acute, bacterial
infection that occurs when pathogens colonize the
Accepted for publication September 2012
Acknowledgements
We would like to thank Dr. Gregor Reid from the University
of Western Ontario for sending us the full-text articles of his
studies, which were not available online.
Address correspondence to Dr. Alison Fox-Robichaud, David
Braley Research Institute, Thrombosis and Atherosclerosis
Research Institute, DBRI C5-106, 237 Barton Street East,
Hamilton, ON L8L 2X2 Canada
© The Canadian Journal of Urology™; 20(1); February 2013
Results: Data from 294 patients across five studies were
included. There was no statistically significant difference
in the risk for rUTI in patients receiving Lactobacillus
versus controls, as indicated by the pooled risk ratio of
0.85 (95% confidence interval of 0.58-1.25, p = 0.41).
A sensitivity analysis was performed, excluding studies
using ineffective strains and studies testing for safety.
Data from 127 patients in two studies were included. A
statistically significant decrease in rUTI was found in
patients given Lactobacillus, denoted by the pooled risk
ratio of 0.51 (95% confidence interval 0.26-0.99, p = 0.05)
with no statistical heterogeneity (I2 = 0%).
Conclusion: Probiotic strains of Lactobacillus are
safe and effective in preventing rUTI in adult women.
However, more RCTs are required before a definitive
recommendation can be made since the patient population
contributing data to this meta-analysis was small.
Key Words: urinary tract infection, cystitis, probiotics,
Lactobacillus, meta-analysis, systematic review
vagina and ascend into the urinary system. 1 It is
the most common infection in premenopausal adult
women, incurring significant morbidity along with
billions of dollars in health care costs annually. 2
Moreover, approximately 20-30 percent of women
develop recurrent urinary tract infections (rUTIs),3,4
which require multiple courses of antibiotic treatment.5
Currently, the clinically prescribed prophylaxis for
women experiencing frequent recurring infections is a
long term, low dose regimen of antimicrobials such as
trimethoprim-sulfamethoxazole or fluoroquinolones.6
Although this method of prophylaxis has been shown
to reduce the incidence of UTI, the benefit ends when
the antimicrobial regimen is discontinued. There
are also several side effects associated with these
antibiotics, which predominantly include vaginal
6607
Lactobacillus for preventing recurrent urinary tract infections in women: meta-analysis
itching, skin rash and/or nausea.7 Furthermore,
antibiotic resistance among uropathogens has been
shown to increase in response to long term use.8,9 Thus,
there is need for alternative prophylactic measures.
Probiotics, defined by the World Health
Organization and Food and Agriculture Organization
of the United Nations as “live microorganisms which
when administered in adequate amounts confer a
health benefit on the host”,10 may be an acceptable
alternative to antimicrobials. Specifically, Lactobacillus
probiotics have been examined for years as a possible
prophylaxis for rUTI. In fact, several indigenous
species of lactobacilli are found in the vaginal
flora of healthy women and these lactobacilli are
thought to play a protective role against pathogenic
colonization.11 Probiotic Lactobacillus strains may
prevent rUTI through a number of conferred benefits:11
1) by restoring balance to the vaginal flora after
antimicrobial treatment for an initial UTI, 2) by helping
to maintain a normal vaginal pH of < 4.5 through lactic
acid production, and 3) by producing the microbicidal
compound H2O2. However, there is no clear evidence
in support of a specific strain or dosage as the most
beneficial, and there is no definitive evidence that these
probiotics are able to prevent rUTI.
Very few clinical trials have tested Lactobacillus
for prevention of rUTI, and these studies are small
in size, making it impractical to draw conclusions
about effectiveness from any single trial. Only one
previous systematic review12 analyzed Lactobacillus
for prevention of rUTI, and new evidence appeared in
the literature13 since the inconclusive findings of this
review were published. Furthermore, no meta-analysis
has been performed on the use of probiotics to prevent
rUTI. Therefore, we performed a systematic review
and meta-analysis of randomized clinical trials (RCTs)
to determine whether probiotic strains of Lactobacillus
are safe and effective in preventing rUTIs.
Materials and methods
We performed this systematic review and meta-
analysis using Cochrane Collaboration methodology
to evaluate the effectiveness of Lactobacillus probiotics
in preventing rUTI.
Search strategy
The primary electronic search was performed using
PubMed and Ovid for the databases MEDLINE and
EMBASE, respectively. PubMed was searched from
inception to July 9, 2012 using combinations of the
following terms: Lactobacillus, probiotic, lactic acid
bacteria, or lactobacilli; and urinary infection, urinary
6608
tract infection, recurrent urinary tract infection, cystitis,
UTI, or rUTI. Ovid included articles from 1974 to July 9,
2012 with combinations of the following search terms:
cystitis, urinary tract infection, or recurrent urinary tract
infection; and probiotic agent, Lactobacillus, or lactic acid
bacterium. No restrictions were placed on the electronic
searches. A secondary search was performed using the
reference lists of relevant articles found electronically,
and the reference list of one previous systematic
review,12 that examined Lactobacillus as a prophylactic
agent in several different urogenital infections.
Inclusion criteria
We searched for parallel group RCTs comparing
Lactobacillus with placebo or other prophylactic
regimens for rUTI. Studies were eligible if they included
a population of premenopausal adult women with a
history of prior UTI (defined as one or more UTIs within
the last 12 months before entering a study).
Study selection
Two of the reviewers screened the titles and abstracts
of articles retrieved through the electronic search, and
found full text articles for relevant studies. The kappa
statistic was used to quantify the degree of agreement
between the reviewers’ independent searches. The same
reviewers also manually scanned the reference lists of
relevant studies for the secondary search. Study authors
were contacted if their full study was not available
through other sources. All four reviewers assessed all
relevant studies against the inclusion criteria.
Risk of bias and data appraisal
All of the articles were evaluated according to the
Cochrane Collaboration’s tool for assessing risk of
bias14 to determine internal validity, with conflicting
judgments resolved. Each trial was judged for risk of
bias associated with the method of sequence generation
(selection bias), allocation concealment (selection bias),
blinding of participants and personnel (performance
bias), blinding of outcome assessment (detection
bias), addressing incomplete outcome data (attrition
bias), and outcome reporting. Information regarding
population characteristics, strain of Lactobacillus, dose
and length of treatment, duration of follow up, and
outcomes was extracted and summarized in a study
characteristics table. The primary outcome for this
meta-analysis was the incidence of at least one rUTI.
The secondary outcome was adverse events, which we
analyzed qualitatively.
Data analysis
For each individual study, risk ratios (RRs) with 95%
© The Canadian Journal of Urology™; 20(1); February 2013

confidence intervals (CIs) were calculated using per
protocol analysis, where the event was one or more
rUTI experienced by a patient during the complete
study period. The random-effects model for meta-
analysis was used to combine the dichotomous
outcomes of studies into a pooled RR. Statistical
heterogeneity among the studies was assessed using
the I2 statistic, where I2 values of 25%, 50% and 75%
indicate low, moderate, and high heterogeneity,
respectively.15 The number needed to treat (NNT)
was calculated using an assumed control event rate
of 30% for rUTI. Forrest plots were generated using
Cochrane Collaboration’s RevMan version 5.1. Two
pooled analyses were performed with this software.
The first consisted of all studies meeting the inclusion
criteria for the search. The second was an a priori
sensitivity analysis, which included studies that tested
specifically for the efficacy of probiotic Lactobacillus in
preventing rUTI.
Figure 1. Flow chart depicting literature search
© The Canadian Journal of Urology™; 20(1); February 2013
GRIN ET AL.
Results
Search results
The electronic search retrieved 744 articles (including
duplicates across databases). After screening titles and
abstracts, a total of seven full-text articles13,16-21 were
evaluated. Two of these articles20,21 were excluded
because they did not meet the a priori inclusion criteria.
One additional study22 was found by searching the
reference lists of the seven articles mentioned above.
This study was included in the systematic review,
but excluded from meta-analysis because the study
compared two treatment groups of Lactobacillus and
Lactobacillus Growth Factor. As a result, five studies13,16-19
randomizing 294 patients to Lactobacillus treatment or
control groups were included in the meta-analysis. The
kappa statistic for agreement among reviewers in their
independent searches was equal to 1. The results of the
search are shown in Figure 1.
6609
Lactobacillus for preventing recurrent urinary tract infections in women: meta-analysis

TABLE 1. Characteristics of included studies

Study Type of study Blinding All Patients Patient description

Reference (control type) patients included
(n) (pooled
analyses)
Reid et al19 Randomized, Double 41 34 Pre-menopausal adult women with an
placebo blind acute, uncomplicated lower UTI
controlled trial
Baerheim et al18 Randomized, Double 48 47 Women ages 18-50 with ≥ 3 UTIs in prior 12
placebo blind months and no UTI at study entry
controlled trial
Reid et al22 Randomized Double 55 n/a, not Pre-menopausal adult women with ≥ 4 UTIs
trial (two blind pooled in prior 12 months, and no UTI at study entry
intervention with
comparison other
without placebo) studies
Kontiokari Randomized None 150 90 Adult women with current UTI
et al17 trial, three arms caused by Escherichia coli
(Lactobacillus,
cranberry, open
control)
Czaja et al16 Randomized, Double 30 30 Pre-menopausal adult women with ≥ 3 UTIs
placebo blind in prior 12 months or ≥ 2 UTIs in prior 6 months
controlled trial
Stapleton et al13 Randomized, Double 100 96 Pre-menopausal adult women with an acute,
placebo blind uncomplicated lower UTI and ≥ 1 UTI treated
controlled trial within prior 12 months

Study characteristics and risk of bias assessment
The characteristics of the included studies are shown in
Tables 1 and 2. The risk of bias assessment for eligible
studies is shown in Table 3. Two of the studies17,22
showed high risk of bias after evaluation using the
Cochrane Collaboration’s risk of bias tool. The study by
Kontiokari et al was not blinded, and therefore exhibits a
high risk of performance and detection bias. The 1995
study by Reid et al was classified as being at high risk of
attrition bias due to the very high dropout rate of 22%.

Figure 2. Forest plot of studies meeting the search criteria. Events = patients acquiring one or more recurrent
UTIs; CI = Confidence Interval; Random = Random-Effects Model; M-H = Mantel-Haenszel; DF = degrees of freedom;
I2 = heterogeneity.

6610 © The Canadian Journal of Urology™; 20(1); February 2013

 GRIN ET AL.

TABLE 2. Characteristics of included studies (continued)

Study Lactobacillus Dose and Length of Duration of RR (95% CI),

Reference administration strain treatment follow up p value
method
Reid et al19 UTI treated with > 1.6 x 109 Twice 6 months 0.45 (0.15-1.40)
antimicrobials for CFU/suppository weekly for p = 0.2682
first 3 days, followed Lactobacillus 2 weeks, then
by Lactobacillus rhamnosus GR-1 at the end of
vaginal suppositories and Lactobacillus each week for
fermentum B-54 the next 2 months
Baerheim et al18 Vaginal > 7.5 x 108 Twice weekly 6 months 0.88 (0.48-1.62)
suppositories CFU/suppository for 26 weeks p = 0.9057
Lactobacillus casei
v rhamnosus LCR35
Reid et al22 Vaginal > 1 x 109 Weekly for 12 months n/a,
suppositories CFU/suppository 12 months no control
L. rhamnosus GR-1
and L. fermentum B-54
Kontiokari et al17 UTI treated with > 4 x 1010 5 days per 12 months 1.11 (0.70-1.76)
antimicrobials until CFU/100 mL week for p = 0.8320
eradicated, followed drink 12 months
by an oral drink of L. rhamnosus GG
Lactobacillus
Czaja et al16 Vaginal 5 x 108 Daily for 5 4 weeks 5.00 (0.26-96.13)
suppositories CFU/suppository days p = 0.4642
Stapleton et al13 UTI treated with 108 CFUs/mL Daily for 5 10 weeks 0.54 (0.24-1.23)
antimicrobials, followed in suppository days, then p = 0.2089
by vaginal suppositories Lactobacillus once weekly
starting 7-10 days later crispatus CTV-05 for 10 weeks

Quantitative data synthesis
The pooled analysis for studies meeting the search
criteria included 294 patients from five RCTs,13,16-19
Figure 2. The use of Lactobacillus was associated with
a trend toward reduction of risk of rUTI (RR 0.85; 95%
CI 0.58-1.25, p = 0.41; I2 = 19%), but these results were
not statistically significant.
A sensitivity analysis, which included patients from
two RCTs, showed that the use of Lactobacillus was
associated with a significant reduction in the risk of

Figure 3. Forest plot of studies testing for efficacy of Lactobacillus probiotics. Events = patients acquiring one
or more recurrent UTIs; CI = Confidence Interval; Random = Random-Effects Model; M-H = Mantel-Haenszel;
DF = degrees of freedom; I2 = heterogeneity.

© The Canadian Journal of Urology™; 20(1); February 2013 6611

Lactobacillus for preventing recurrent urinary tract infections in women: meta-analysis
TABLE 3. Risk of bias assessments
= Low risk of bias
= Unclear risk of bias
= High risk of bias
rUTI (RR 0.51; 95% CI 0.26-0.99, p = 0.05, I2 = 0%) when
compared with control, Figure 3. This translates to a
NNT of 7 to prevent one UTI, for an assumed control
rate of 30%. The study by Czaja et al16 was excluded
from this analysis since it was a safety trial, which did
not test for the efficacy of Lactobacillus intervention. The
study by Baerheim et al was also excluded as there was
no vaginal colonization established in this study, where
Lactobacillus casei var. rhamnosus LCR35 was examined.18
Furthermore, this strain has questionable probiotic
properties in the urogenital environment: only one in
vitro study23 evaluated the potential of this strain as a
6612
urogenital probiotic, and there have been no clinical
trials testing its efficacy. The study by Kontiokari et al17
was excluded because the administration of Lactobacillus
rhamnosus GG orally has since been proven ineffective
in establishing vaginal colonization.24,25
Secondary outcomes
The two studies by Reid et al reported no adverse
events. 19,22 Adverse events in the 2011 study by
Stapleton et al were reported by 56% of patients in the
Lactobacillus treatment group and by 50% of patients in
the placebo group, the most common of which were
vaginal discharge, itching or moderate abdominal
discomfort.13 Baerheim et al reported that four patients
(16%) in the Lactobacillus treatment group and one
patient (5%) in the placebo group complained about
discharge on the day following suppository insertion,
with no other side effects reported.18 In the phase I trial
by Czaja et al, patients reported experiencing mainly
abnormal vaginal discharge, external genital irritation,
and vaginal candidiasis.16 Finally, Kontiokari et al
reported no adverse events.17
Discussion
The current systematic review was performed with
meta-analysis to determine if Lactobacillus probiotics
are effective in preventing rUTI. Our meta-analysis
consisted of data from 294 patients across five studies.
The results of this analysis show no statistically
significant evidence that Lactobacillus probiotics prevent
rUTI. Our sensitivity analysis included data from 127
patients across two studies that used probiotic strains of
Lactobacillus shown to colonize the vaginal epithelium.
The evidence from this analysis suggests that probiotic
Lactobacillus strains prevent rUTI. The removal of
studies with strains that do not achieve vaginal
colonization is an important consideration. When
quantifying the effect of Lactobacillus probiotics, these
studies may have falsely skewed the pooled estimate
towards lack of effect by simply using an ineffective
strain that by definition is not a probiotic.
This review focused on a population of premenopausal
women to increase the specificity of the results and
because few, if any, RCTs have tested Lactobacillus
probiotics for rUTI in postmenopausal women, pregnant
women or the pediatric population. Also, common risk
factors for UTI in premenopausal women are different
from those in other groups. These include recent sexual
intercourse, use of a diaphragm with spermicide or
spermicidal condoms, a history of UTI, and recent
antimicrobial use.26-29 A multivariate analysis by Scholes
et al found high frequency of sexual intercourse to be
© The Canadian Journal of Urology™; 20(1); February 2013

the greatest risk factor for UTI, although the reason
for this remains unclear.26 The remaining risk factors
all appear to either cause or result from a depletion
of lactobacilli in the vaginal microbiota, which allows
uropathogens to colonize the vagina and later ascend into
the urinary tract.30 The use of Lactobacillus suppositories
could reduce the risk caused by these factors by simply
restoring balance to the vaginal microbiota, and thus
restoring protection against uropathogens at the point
of entry. Additionally, it is known that all lactobacilli
produce lactic acid, which helps maintain a healthy low
vaginal pH of approximately 4.5 that in turn inhibits
pathogen survival.11 Also, certain probiotic strains of
Lactobacillus provide additional benefits. Specifically,
Lactobacillus rhamnosus GR-1 and Lactobacillus crispatus
CTV-05 produce H2O2, a strong antimicrobial that induces
membrane stress on uropathogenic bacteria.11,31 Such
stress has been shown to prevent growth of Escherichia coli
and its adhesion to the vaginal epithelium.11 Along with
L. rhamnosus GR-1 and L. crispatus CTV-05, Lactobacillus
fermentum B-54 was also shown in clinical trials to be
highly capable of colonization and survival within the
vaginal environment.13,19,22
Although promising, the current literature is
inconclusive regarding the use of probiotics for
preventing rUTIs since no large clinical trials have
been performed. Several recent reviews suggested
that Lactobacillus probiotics are safe and effective in
preventing rUTIs, but cannot be recommended clinically
due to absence of evidence from large clinical trials.32-34
The studies we reviewed confirm that Lactobacillus
suppositories could be used safely; some patients
experienced only mild side effects. Moreover, these
side effects can be attributed to the suppository vehicle
of administration rather than Lactobacillus itself, since
both control and experimental groups experienced a
similar rate of side effects. The only study to administer
Lactobacillus orally found that patients experienced no
side effects, further supporting our observation that the
suppository method of administration is responsible
for adverse events. Additionally, L. rhamnosus GR-1
has been shown to colonize the vagina after oral
administration of > 109 CFU twice daily for 14 days in
a different study.21 Therefore, oral administration may
be a feasible solution to the occurrence of side effects
and could result in better patient compliance.
There are several strengths and limitations
associated with our analysis. The rigorous standards
we set in our search criteria yielded studies involving,
specifically, a high-risk population of premenopausal
women. Some background research on specific strains
allowed us to perform a sensitivity analysis that only
included probiotic strains proven to confer benefits in
© The Canadian Journal of Urology™; 20(1); February 2013
GRIN ET AL.
the urogenital environment. Through this analysis,
homogeneity in the probiotic administration method
was also achieved since the single study testing
oral Lactobacillus used an ineffective strain, and was
consequently removed. Additionally, the two studies
included in the sensitivity analysis did not exhibit high
risk of bias in their methodology. Although decreased
incidence of rUTI in patients given Lactobacillus was
found through this analysis, there are some limitations
that must be considered. This analysis included two
studies with only 127 patients combined. Also, there
is considerable heterogeneity in study duration. The
study lengths ranged from 4 weeks to 12 months,
with those included in the sensitivity analysis being
10 weeks and 12 months long.
Conclusion
Further research is required to determine whether
probiotic strains of Lactobacillus prevent rUTI in
premenopausal women. Our analysis suggests that
suppositories containing L. crispatus CTV-05 or a
combination of L. rhamnosus GR-1 and L. fermentum B-54
are most effective. Therefore future RCTs should study
these strains, over a 6 to 12 month period, to build upon
the existing evidence for efficacy of these probiotics
in prevention of rUTI. We also found that no serious
adverse events have been caused by Lactobacillus in
studies involving healthy premenopausal women,
which supports the case for carrying out additional
clinical trials. Moreover, studies need to address
whether oral administration of the Lactobacillus strains
mentioned above are also effective and whether this
mode of administration eliminates side effects while
increasing patient compliance. Until further research
is completed, these probiotic strains of Lactobacillus
delivered in suppositories may be considered, but
not definitively recommended, as a safe alternative to
antimicrobials for UTI prophylaxis in high risk women
when antimicrobial resistance is an issue.
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© The Canadian Journal of Urology™; 20(1); February 2013